This invention relates to medicinal chemistry and pharmacology. More particularly, it relates to antagonists of the adenosine receptors, pharmaceutical compositions comprising these compounds and methods of making and using the same in the treatment of diseases.
Adenosine is a ubiquitous biochemical messenger. Adenosine binds to and activates seven-transmembrane spanning G-protein coupled receptors, eliciting a variety of physiological responses. Adenosine receptors are divided into four known subtypes (i.e., A1, A2a, A2b, and A3). These receptor subtypes mediate different, and sometimes opposing, effects. Activation of the adenosine A1 receptor, for example, elicits an increase in renal vascular resistance, while activation of the adenosine A2a receptor elicits a decrease in renal vascular resistance.
In most mammalian organ systems, periods of metabolic stress result in significant increases in the concentration of adenosine in the tissue. The heart, for instance, produces and releases adenosine to mediate adaptive responses to stress, such as reductions in heart rate and coronary vasodilatation. Likewise, adenosine concentrations in kidneys increase in response to hypoxia, metabolic stress and many nephrotoxic substances. The kidneys also produce adenosine constitutively. The kidneys adjust the amount of constitutively produced adenosine in order to regulate glomerular filtration and electrolyte reabsorption. Regarding control of glomerular filtration, activation of A1 receptors leads to constriction of afferent arterioles, while activation of A2a receptors leads to dilatation of efferent arterioles. Activation of A2a receptors exerts vasodilatory effects on the afferent arteriole. Overall, the effect of activation of these glomerular adenosine receptors is to reduce glomerular filtration rate. In addition, A1 adenosine receptors are located in the proximal tubule and distal tubular sites. Activation of these receptors stimulates sodium reabsorption from the tubular lumen. Accordingly, blocking the effects of adenosine on these receptors produces a rise in glomerular filtration rate and an increase in sodium excretion.
The invention is based on the discovery that compounds of Formula I and II are potent and selective inhibitors of particular subtypes of adenosine receptors. Based on this discovery, the invention features adenosine antagonists useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable. In general, the invention features highly potent and selective antagonists of the adenosine A1 receptor.
The invention features compounds of formula I or II: 
wherein
R1 and R2 are independently selected from the group consisting of:
a) hydrogen;
b) alkyl, alkenyl or alkynyl, wherein said alkyl, alkenyl, or alkynyl is either unsubstituted or functionalized with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and
c) aryl or substituted aryl;
R3 is selected from the group consisting of:
(a) a bicyclic, tricyclic or pentacyclic group selected from the group consisting of: 
xe2x80x83wherein the bicyclic, tricyclic or pentacyclic group is either unsubstituted or functionalized with one or more substituents selected from the group consisting of:
(i) alkyl, alkenyl and alkynyl; wherein each alkyl, alkenyl or alkynyl group is either unsubstituted or functionalized with one or more substituents selected from the group consisting of (alkoxycarbonyl)aralkylcarbamoyl, (amino)(R5)acylhydrazinylcarbonyl, (amino)(R5)acyloxycarboxy, (hydroxy)(carboalkoxy)alkylcarbamoyl, acylaminoalkylamino, acyloxy, aldehydo, alkenoxy, alkenylamino, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylamino, alkoxycarbonylaminoacyloxy, alkoxycarbonylaminoalkylamino, alkylamino, alkylaminoalkylamino, alkylcarbamoyl, alkylphosphono, alkylsulfonylamino, alkylsulfonyloxy, amino, aminoacyloxy, aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl, aminoalkylheterocyclylalkylcarbamoyl, aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl, aralkoxycarbonyl, aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino, arylsulfonyloxy, carbamoyl, carbonyl, cyano, cyanoalkylcarbamoyl, cycloalkylamino, dialkylamino, dialkylaminoalkylamino, dialkylaminoalkylcarbamoyl, dialkylphosphono, haloalkylsulfonylamino, halogen, heterocyclyl, heterocyclylalkylamino, heterocyclylcarbamoyl, hydroxy, hydroxyalkylsulfonylamino, oximino, phosphate, phosphono, xe2x80x94R5, R5-alkoxy, R5-alkyl(alkyl)amino, R5-alkylalkylcarbamoyl, R5-alkylamino, R5-alkylcarbamoyl, R5-alkylsulfonyl, R5-alkylsulfonylamino, R5-alkylthio, R5-heterocyclylcarbonyl, substituted aralkylamino, substituted arylcarboxyalkoxycarbonyl, substituted arylsulfonylaminoalkylamino, substituted heteroarylsulfonylamino, substituted heterocyclyl, substituted heterocyclylaminoalkylamino, substituted heterocyclylsulfonylamino, sulfoxyacylamino, thiocarbamoyl, trifluoromethyl; and
(ii) (alkoxycarbonyl)aralkylcarbamoyl, (amino)(R5)acylhydrazinylcarbonyl, (amino)(R5)acyloxycarboxy, (hydroxy)(carboalkoxy)alkylcarbamoyl, acylaminoalkylamino, acyloxy, aldehydo, alkenoxy, alkenylamino, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylamino, alkoxycarbonylaminoacyloxy, alkoxycarbonylaminoalkylamino, alkylamino, alkylaminoalkylamino, alkylcarbamoyl, alkylphosphono, alkylsulfonylamino, alkylsulfonyloxy, amino, aminoacyloxy, aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl, aminoalkylheterocyclylalkylcarbamoyl, aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl, aralkoxycarbonyl, aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino, arylsulfonyloxy, carbamoyl, carbonyl, cyano, cyanoalkylcarbamoyl, cycloalkylamino, dialkylamino, dialkylaminoalkylamino, dialkylaminoalkylcarbamoyl, dialkylphosphono, haloalkylsulfonylamino, halogen, heterocyclyl, heterocyclylalkylamino, heterocyclylcarbamoyl, hydroxy, hydroxyalkylsulfonylamino, oximino, phosphate, phosphono, xe2x80x94R5, R5-alkoxy, R5-alkyl(alkyl)amino, R5-alkylalkylcarbamoyl, R5-alkylamino, R5-alkylcarbamoyl, R5-alkylsulfonyl, R5-alkylsulfonylamino, R5-alkylthio, R5-heterocyclylcarbonyl, substituted aralkylamino, substituted arylcarboxyalkoxycarbonyl, substituted arylsulfonylaminoalkylamino, substituted heteroarylsulfonylamino, substituted heterocyclyl, substituted heterocyclylaminoalkylamino, substituted heterocyclylsulfonylamino, sulfoxyacylamino, thiocarbamoyl, trifluoromethyl;
R4 is selected from the group consisting of hydrogen, C1-4-alkyl, C1-4-alkyl-CO2H, and phenyl, wherein the C1-4-alkyl, C1-4-alkyl-CO2H, and phenyl groups are either unsubstituted or functionalized with one to three substituents selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94OMe, xe2x80x94NH2, NO2, benzyl, and benzyl functionalized with one to three substituents selected from the group consisting of halogen, xe2x80x94OH, xe2x80x94OMe, xe2x80x94NH2, and xe2x80x94NO2;
R5 is selected from the group consisting of xe2x80x94(CR1R2)nCOOH, xe2x80x94C(CF3)2OH, xe2x80x94CONHNHSO2CF3, xe2x80x94CONHOR4, xe2x80x94CONHSO2R4, xe2x80x94CONHS2NHR4, xe2x80x94C(OH)R4PO3H2, xe2x80x94NHCOCF3, xe2x80x94NHCONHSO2R4, xe2x80x94NHPO3H2, xe2x80x94NHSO2R4, xe2x80x94NHSO2NHCOR4, xe2x80x94OPO3H2, xe2x80x94OSO3H, xe2x80x94PO(OH)R4, xe2x80x94PO3H2, xe2x80x94SO3H, xe2x80x94SO2NHR4, xe2x80x94SO3NHCOR4, xe2x80x94SO3NHCONHCO2R4, and the following: 
A is selected from the group consisting of xe2x80x94CHxe2x95x90CH, 13 (CH)mxe2x80x94(CH)m,, CHxe2x95x90CHxe2x80x94CH2, and
xe2x80x94CH2xe2x80x94CHxe2x95x90CH;
m=1 or 2;
X is O or S;
Z is selected from the group consisting of a single bond, xe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94, xe2x80x94O(CH2)1-2xe2x80x94, xe2x80x94CH2OCH2xe2x80x94, xe2x80x94(CH2)1-2Oxe2x80x94, xe2x80x94CHxe2x95x90CHCH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, and xe2x80x94CH2CHxe2x95x90CHxe2x80x94; and
R6 is selected from the group consisting of hydrogen, alkyl, acyl, alkylsufonyl, aralkyl, substituted aralkyl, substituted alkyl, and heterocyclyl; and
R7 is selected from the group consisting of:
a) hydrogen;
b) alkyl, alkenyl of not less than 3 carbons, or alkynyl of not less than 3 carbons; wherein said alkyl, alkenyl or alkynyl is either unsubstituted or functionalized with one or more substitutents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and
c) aryl or substituted aryl;
d) alkylaryl or alkyl substituted aryl.
The compounds of Formula I or II optionally can be in forms such as an achiral compound, a racemate, an optically active compound, a pure diastereomer, a mixture of diastereomers, or a pharmacologically acceptable addition salt. In certain preferred embodiments, the compounds of the invention are compounds of Formula I or II wherein neither of R1 and R2 are hydrogen, that is, each of R1 and R2 are independently selected from the group consisting of
a) alkyl, alkenyl or alkynyl, wherein said alkyl, alkenyl, or alkynyl is either unsubstituted or functionalized with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and
b) aryl or substituted aryl.
More preferably, at least one of R1 and R2 is alkyl. In yet other preferred embodiments,
A is xe2x80x94(CH)mxe2x80x94(CH)m.
R7 is alkyl in other preferred embodiments, and Z is preferably a single bond.
Preferred compounds of this invention are:
2-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-7-isopropyl-4-propyl-1,4,6,7-tetrahydro-1,3,4,5a,8-pentaaza-as-indacen-5-one (compound 1);
7-Ethyl-2-(4-hydroxy-bicyclo[2.2.2]oct-1-yl)-4-propyl-1,4,6,7-tetrahydro-1,3,4,5a,8-pentaaza-as-indacen-5-one (compound 2);
3-[4-(7-Ethyl-5-oxo-4-propyl-4,5,6,7-tetrahydro-1H-1,3,4,5a,8-pentaaza-as-indacen-2-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid (compound 3);
2-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-7-methyl-4-propyl-1,4,6,7-tetrahydro-1,3,4,5a,8-pentaaza-as-indacen-5-one (compound 4); and
3-[4-(7-Isopropyl-5-oxo-4-propyl-4,5,6,7-tetrahydro-1H-1,3,4,5a,8-pentaaza-as-indacen-2-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid (compound 5).
The compounds of this invention can be modified to enhance desired properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and/or alter rate of excretion. Examples of these modifications include, but are not limited to, esterification with polyethylene glycols, derivatization with pivolates or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings, and heteroatom-substitution in aromatic rings.
The invention also features a pharmaceutical composition including any of the above compounds, alone or in a combination, together with a suitable excipient.
The invention also features a method of treating a patient displaying signs or symptoms of a disease or disorder wherein activation of A1 adenosine receptors plays a causative role in the disease or disorder. The method includes administering to the patient an effective amount of any of the above compounds. The disease or disorder can be, for example, systemic hypertension, renal failure, diabetes, asthma, an edematous condition, congestive heart failure, or renal dysfunction(e.g., renal dysfunction occurring as a side effect of a diuretic used to treat congestive heart failure, or renal toxicity occurring as a side effect of treatment with chemotherapeutic agents).
Compounds of the invention offer advantages, including the following. For example, (1) they can be used in low doses to minimize the likelihood of side effects and (2) they can be incorporated into numerous dosage forms including, but not limited to, pills, tablets, capsules, aerosols, suppositories, liquid formulations for ingestion or injection, dietary supplements, or topical preparations. In addition to human medical applications, the compounds of the invention can be used in the veterinary treatment of animals. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intramuscular or subcutaneous administration.
This invention also feature a process for preparing the above compounds comprising the steps of: a) alkylating a thioketone to produce a thioether; b) reacting the thioether with a substituted amino alcohol to produce an alcohol intermediate; and c) cyclizing the alcohol intermediate to produce a cyclized product.
In some embodiments the above process further comprises the step of: a) converting the cyclized product to a carboxylic acid derivative. In some embodiments, the process comprises the steps of: a) coupling a diamino uracil with bicyclo[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester to produce an acid; b) reducing the acid to a corresponding alcohol; c) oxidizing the alcohol to an aldehyde; d) coupling the aldehyde with methyl(triphenylphosphoroanylidene) acetate to produce a coupled product; e) converting the coupled product to a thioketone; f) alkylating the thioketone to produce a thioether; g) reacting the thioether with a substituted amino alcohol to produce an alcohol intermediate; and h) cyclizing the alcohol intermediate to produce a cyclized product; and i) converting the cyclized product to a carboxylic acid derivative.
In some embodiments, the process comprises the steps of a) coupling a diamino uracil with bicyclo[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester to produce an acid; b) esterifying the acid to a corresponding ester; c) converting the ester to produce a thioketone; d) alkylating the thioketone to produce a thioether; e) reacting the thioether with a substituted amino alcohol to produce an alcohol intermediate; and f) cyclizing the alcohol intermediate to produce a cyclized product.and g) converting the cyclized product to a carboxylic acid derivative.
In some embodiments, the process comprises the steps of: a) nitrosating 6-amino-1-propyl-1H-pyrimidine-2,4-dione to produce a nitroso intermediate; b) reducing the nitroso intermediate to produce the corresponding diamino uracil; c) converting the diamino uracil to an amine salt; d) coupling the amine salt to 4-hydroxy-bicyclo[2.2.2]octane-1-carboxylic acid to produce a coupled product; and e) converting the coupled product to a thioketone; f) alkylating the thioketone to produce a thioether; g) reacting the thioether with a substituted amino alcohol to produce an alcohol intermediate; and h) cyclizing the alcohol intermediate to produce a cyclized product.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Throughout this specification, the word xe2x80x9ccomprisexe2x80x9d or variations such as xe2x80x9ccomprisesxe2x80x9d or xe2x80x9ccomprisingxe2x80x9d will be understood to imply the inclusion of a stated integer or groups of integers but not the exclusion of any other integer or group of integers.
As used herein, xe2x80x9calkenylxe2x80x9d group is an aliphatic carbon group that has at least one double bond. An alkenyl group can be straight or branched, and can have, for example, from 3 to 6 carbon atoms in a chain and 1 or 2 double bonds. Examples of alkenyl groups include, but are not limited to, allyl and isoprenyl.
As used herein, xe2x80x9calkynylxe2x80x9d group is an aliphatic carbon group that has at least one triple bond. An alkynyl group can be straight or branched, and can have, for example, from 3 to 6 carbon atoms in a chain and 1 to 2 triple bonds. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl.
As used herein, xe2x80x9carylxe2x80x9d group is a phenyl or naphthyl group, or a derivative thereof. A xe2x80x9csubstituted arylxe2x80x9d group is an aryl group that is substituted with one or more substituents such as alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkylamino, dialkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, trihaloalkyl, carboxyalkyl, sulfoxy, or carbamoyl.
As used herein, xe2x80x9caralkylxe2x80x9d group is an alkyl group that is substituted with an aryl group. An example of an aralkyl group is benzyl.
As used herein, xe2x80x9ccycloalkylxe2x80x9d group is an aliphatic ring of, for example, 3 to 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl and cyclohexyl.
As used herein, xe2x80x9cacylxe2x80x9d group is a straight or branched alkyl-C(xe2x95x90O)xe2x80x94 group or a formyl group. Examples of acyl groups include alkanoyl groups (e.g., having from 1 to 6 carbon atoms in the alkyl group). Acetyl and pivaloyl are examples of acyl groups. Acyl groups may be substituted or unsubstituted.
As used herein, xe2x80x9ccarbamoylxe2x80x9d group is a group having the structure H2Nxe2x80x94CO2xe2x80x94. xe2x80x9cAlkylcarbamoylxe2x80x9d and xe2x80x9cdialkylcarbamoylxe2x80x9d refer to carbamoyl groups in which the nitrogen has one or two alkyl groups attached in place of the hydrogens, respectively. By analogy, xe2x80x9carylcarbamoylxe2x80x9d and xe2x80x9carylalkylcarbamoylxe2x80x9d groups include an aryl group in place of one of the hydrogens and, in the latter case, an alkyl group in place of the second hydrogen.
As used herein, xe2x80x9ccarboxylxe2x80x9d group is a xe2x80x94COOH group.
As used herein, xe2x80x9calkoxyxe2x80x9d group is an alkyl-Oxe2x80x94 group in which xe2x80x9calkylxe2x80x9d is as previously described.
As used herein, xe2x80x9calkoxyalkylxe2x80x9d group is an alkyl group as previously described, with a hydrogen replaced by an alkoxy group, as previously described.
As used herein, xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d group is fluorine, chlorine, bromine or iodine.
As used herein, xe2x80x9cheterocyclylxe2x80x9d group is a 5 to about 10 membered ring structure, in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O, S. A heterocyclyl group can be aromatic or non-aromatic, i.e., can be saturated, or can be partially or fully unsaturated. Examples of heterocyclyl groups include pyridyl, imidazolyl, furanyl, thienyl, thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, indolyl, indolinyl, isoindolinyl, piperidinyl, pyrimidinyl, piperazinyl, isoxazolyl, isoxazolidinyl, tetrazolyl, and benzimidazolyl.
As used herein, xe2x80x9csubstituted heterocyclylxe2x80x9d group is a heterocyclyl group wherein one or more hydrogens are replaced by substituents such as alkoxy, alkylamino, dialkylamino, carbalkoxy, carbamoyl, cyano, halo, trihalomethyl, hydroxy, carbonyl, thiocarbonyl, hydroxyalkyl or nitro.
As used herein, xe2x80x9chydroxyalkylxe2x80x9d means an alkyl group substituted by a hydroxy group.
As used herein, xe2x80x9csulfamoylxe2x80x9d group has the structure xe2x80x94S(O)2NH2. xe2x80x9cAlkylsulfamoylxe2x80x9d and xe2x80x9cdialkylsulfamoylxe2x80x9d refer to sulfamoyl groups in which the nitrogen has one or two alkyl groups attached in place of the hydrogens, respectively. By analogy, xe2x80x9carylsulfamoylxe2x80x9d and xe2x80x9carylalkylsulfamoylxe2x80x9d groups include an aryl group in place of one of the hydrogens and, in the latter case, an alkyl group in place of the second hydrogen.
As used herein, an xe2x80x9cantagonistxe2x80x9d is a molecule that binds to a receptor without activating the receptor. It competes with the endogenous ligand for this binding site and, thus, reduces the ability of the endogenous ligand to stimulate the receptor.
In the context of the present invention, a xe2x80x9cselective antagonistxe2x80x9d is an antagonist that binds to a specific subtype of adenosine receptor with higher affinity than to other adenosine receptor subtypes. The antagonists of the invention can, for example, have high affinity for A1 receptors and are selective, having (a) nanomolar binding affinity for the A1 receptor and (b) at least 10 times, more preferably 50 times, and most preferably at least 100 times, greater affinity for the A1 receptor subtype than for any other receptor subtype.
As used herein, xe2x80x9cpharmaceutically effective amountxe2x80x9d means an amount effective in treating or preventing a condition characterized by an elevated adenosine concentration and/or increased sensitivity to adenosine. As used herein, the term xe2x80x9cpatientxe2x80x9d means a mammal, including a human.
As used herein, xe2x80x9cpharmaceutically acceptable carrier or adjuvantxe2x80x9d means a non-toxic carrier or adjuvant that may be administered to an animal, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
In general, the invention relates to potent and selective antagonists of the adenosine A1 receptor. Exemplary compounds of the invention are described in Table 1. The compounds taught herein exhibit IC50""s against the Rat A1 receptor in the range of from about 7 to about 1095.
Synthesis of the Adenosine Antagonist Compounds
The compounds of the invention may be prepared by a number of known methods. For example, these compounds can be prepared by methods taught in Suzuki, F. et al. J. Med. Chem. 1992, 35, 3581-3583., and/or Shimada, J.; Suzuki, F. Tetrahedron Lett. 1992, 33, 3151-3154.
Three general synthetic schemes for producing the compounds of this invention are described below. 
As can be appreciated by the skilled artisan, the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art.
Uses for the Adenosine Antagonist Compounds
Activation of subtype A1 adenosine receptors elicits many physiological responses, including reductions in renal blood flow, reductions in glomerular filtration rate, and increases in sodium reabsorption in kidney. Activation of A1 adenosine receptors also reduces heart rate, reduces conduction velocity, and reduces contractility. These, and the other effects of activation of A1 adenosine receptors in other organs, are normal regulatory processes. However, these effects become pathological in many disease states. Thus, A1 adeno sine receptor antagonists have extensive application in both prevention and treatment of disease. Diseases that can be prevented and/or treated with A1 adenosine receptor antagonists include diseases and disorders wherein activation of A1 adenosine receptors plays a role in pathophysiology. Examples of such diseases and disorders include, but are not limited to, congestive heart failure,; respiratory disorders (e.g., bronchial asthma, allergic lung diseases); and many diseases for which diuretic treatment is indicated (e.g., acute and chronic renal failure, renal insufficiency, hypertension).
Additionally, the invention provides for the administration of highly selective and potent adenosine A1 receptor antagonists, for example, to elicit a diuretic response when administered alone and to potentiate the diuretic response to traditional diuretics. In addition, administration of A1 adenosine receptor antagonists with traditional diuretics attenuates the reduction of glomerular filtration rate induced by traditional diuretics. This is useful, for example, in treating edematous conditions, such as congestive heart failure and ascites.
Administration of the Adenosine Antagonist Compounds
The compounds can be administered to an animal (e.g., a mammal such as a human, non-human primate, horse, dog, cow, pig, sheep, goat, cat, mouse, rat, guinea pig, rabbit, hamster, gerbil, ferret, lizard, reptile, or bird). The compounds can be administered in any manner suitable for the administration of pharmaceutical compounds, including, but not limited to, pills, tablets, capsules, aerosols, suppositories, liquid formulations for ingestion or injection or for use as eye or ear drops, dietary supplements, and topical preparations. The compounds can be administered orally, intranasally, transdermally, intradermally, vaginally, intraaurally, intraocularly, buccally, rectally, transmucosally, or via inhalation, implantation (e.g., surgically), or intravenous administration.
Optionally, the compounds can be administered in conjunction with a non-adenosine modifying pharmaceutical composition (e.g., in combination with a non-adenosine modifying diuretic as described, for example, in co-pending application PCT/US99/08879 filed Apr. 23, 1999).
Pharmaceutical Compositions
The A1 adenosine receptor antagonists may be formulated into pharmaceutical compositions for administration to animals, including humans. These pharmaceutical compositions, preferably include an amount of A1 adenosine receptor antagonist effective to reduce vasoconstriction or enhance pulmonary hemodynamics and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers useful in these pharmaceutical compositions include, e.g., ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The compositions of the present invention may be administered parenterally, orally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
Parenteral formulations may be a single bolus dose, an infusion or a loading bolus dose followed with a maintenance dose. These compositions may be administered once a day or on an xe2x80x9cas neededxe2x80x9d basis.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically. Topical application can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of A1 adenosine receptor antagonist that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The compositions can be formulated so that a dosage of between 0.01-100 mg/kg body weight of the A1 adenosine receptor antagonist is administered to a patient receiving these compositions. In some ebodiments of the invention, the dosage is 0.1-10 mg/kg body weight. The composition may be administered as a single dose, multiple doses or over an established period of time in an infusion.
A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the particular A1 adenosine receptor antagonist, the patient""s age, body weight, general health, sex, and diet, and the time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated. Judgment of such factors by medical caregivers is within ordinary skill in the art. The amount of antagonist will also depend on the individual patient to be treated, the route of administration, the type of formulation, the characteristics of the compound used, the severity of the disease, and the desired effect. The amounts of antagonists can be determined by pharmacological and pharmacokinetic principles well-known in the art.